Hyperpigmentation and Its Topical Treatments*
C.B. Lynde; J.N. Kraft, MD; C.W. Lynde, MD, FRCPC
Faculty of Medicine, University of Toronto, Toronto, Canada
- Hyperpigmentation is very common and results from excess cutaneous melanin deposition causing a color change:
- Epidermal involvement appears as brown discoloration.
- Dermal deposition is blue-grey.
- Mixed epidermal-dermal depositions are brown-grey.
- Melanin can be deposited in the epidermis or dermis; dermal hyperpigmentation is much more challenging to treat.
- A Wood’s lamp is beneficial for determining the location of melanin deposition.
- Shows enhancement of color contrast in epidermal lesions, but not dermal lesions. The mixed type has enhancement in some areas of lesional skin, but not in others.
- The most common pigmentation disorders for which patients seek treatment are melasma and postinflammatory hyperpigmentation (PIH).
- Multiple topical modalities can be used, and combination topical therapies are the current first-line approach.
- Occurs mainly in women of all racial and ethnic groups, particularly those with Fitzpatrick skin types IV to VI:
- Type IV (olive) - Rarely burns, always tans
- Type V (brown) - Very rarely burns, always tans
- Type VI (black) - Never burns, always tans
- There are multiple factors involved including:
- A genetic predisposition
- Ultraviolet light exposure
- Estrogen exposure, thought to induce melasma
- During pregnancy, which clears within a few months of delivery.
- With use of oral contraceptives and hormone replacement therapy in postmenopausal women. However, discontinuation of these drugs rarely clears this condition.
- Presents as brown to grey macules and patches, with serrated, irregular, and geographic borders. The pigmented patches are usually sharply demarcated and symmetrical.
- Melasma has a predilection for sun exposed areas.
- The three major patterns of distribution are:
- Centrofacial (cheeks, forehead, upper lip, nose, and chin)
- Malar (cheeks and nose)
- Mandibular (rami of mandible).
Postinflammatory Hyperpigmentation (PIH)
- Represents a pathophysiologic response to cutaneous inflammation, e.g., acne, atopic dermatitis, lichen planus, and
- More obvious in patients with brown or black skin with no gender or age predominance.
- Lesions characteristically limited to the site of the preceding inflammation and have indistinct, feathered borders.
- Epidermal hyperpigmentation (e.g., associated with acne) occurs when increased melanin is transferred to keratinocytes.
- Dermal pigmentation (e.g., associated with lichen planus and cutaneous lupus erythematosus) occurs when the basement membrane is disrupted and melanin falls into the dermis and resides within melanophages.
- Initial treatments for PIH should involve an attempt at treating the underlying skin condition.
- Therapeutic goals include
- Inhibiting the formation of melanosomes
- Promoting the degradation of melanosomes
- Retarding the proliferation of melanocytes.
- Sun exposure is an important etiologic factor, therefore all patients should use daily, broad-spectrum, 15 SPF-minimum sunscreens and minimize sun exposure.
- The same treatment principles hold for PIH and melasma.
- Treatment of melasma in pregnant women is routinely deferred until after delivery.
Hydroquinone (HQ) 2%-4%
- Widely used for melasma therapy.
- Patch testing elsewhere on the body, e.g., the upper inner arm, should be done to confirm nonallergenicity prior to attempting a trial of bleaching agents.
- Side-effects include irritant and allergic contact dermatitis, PIH, nail bleaching, and rarely, ochronosis-like pigment.
- Under no circumstances should monobenzylether of hydroquinone or other ethers of HQ be used to treat melasma as they can lead to a permanent loss of melanocytes with the development of a disfiguring confetti-like leukoderma.
- HQ regulatory safety issues may pose availability issues.
- Tretinoin (0.05%-0.1%) reduces pigmentation by inhibiting tyrosinase transcription, and interrupting melanin synthesis.
- Typically takes at least 24 weeks to see clinical improvement.
- May increase pigmentation secondary to irritation.
- May cause erythema and peeling.
- Other retinoids including adapalene, tazarotene and topical isotretinoin have also been used.
Azelaic Acid (15%-20%)
- A reversible inhibitor of tyrosinase.
- May have cytotoxic and antiproliferative effects on melanocytes.
- Was shown to be as effective as HQ 4% without HQ’s side effects.[Balina LM, et al. Int J Dermatol 30:893-5 (1991).]
- Adverse effects include pruritus, mild erythema, scaling, and burning.
Kojic Acid (2%)
- Produced by the fungus Aspergilline oryzae and is a tyrosinase inhibitor.
- Generally equivalent to other therapies but may be more irritating.
- May be effective if a patient has difficulty tolerating other first-line therapies.[Cayce KA, et al. Derm Nursing 16(5):401-6, 413-6 (2004).]
Glycolic Acid (5%-10%)
- An alpha-hydroxy acid
- Reduces pigment by
- thinning the stratum corneum.
- enhancing epidermolysis.
- dispersing melanin in the basal layer of the epidermis.
- increasing collagen synthesis in the dermis.
- Combination therapy is more effective than single agents used alone.
- Kligman formula (HQ 5%, tretinoin 0.1% and dexamethasone 0.1%) is the most widely used combination therapy for melasma worldwide.[Kligman AM, et al. Arch Dermatol 111:40-8 (1975).]
- The combination of azelaic acid with 0.05% tretinoin or 15-20% glycolic acid may produce earlier, more pronounced lightening.[Finlay AY. Br J Dermatol 136:305-14 (1997).]
- Kojic acid 2% combined with HQ 2% was shown to be superior to glycolic acid 10% and HQ 2%.[Lim JT. Dermatol Surg 25:282-4 (1999).]
- • Glycolic acid 5% with either HQ 4% or kojic acid 4% for 3 months proved equally effective with reduction of pigmentation in 51% of patients.[Garcia A, et al. Dermatol Surg 22:443-7 (1996).]
- • Glycolic acid 10% plus HQ 4% in a cream of vitamins C and E and sunscreen was effective in 75% of patients.[Guevara IL, et al. Int J Dermatol 43:966-72 (2003).]
- • A new combination of HQ 4%, tretinoin 0.05%, and fluocinolone acetonide 0.01% (Tri-Luma®) proved effective with 77% of patients showing complete or nearly complete clearing in this multi-centre, randomized, double-blind, control trial.[Taylor SC, et al. Cutis 72:67-72 (2003).]
- Are readily available.
- HQ for OTC use not as effective as stronger prescription formulations.[Halder R, et al. Skin Therapy Lett 9(6):1-3 (2004 Jun-Jul).]
- Alpha and beta hydroxy acid home chemical peels and topical vitamin A are also available.
- New formulation: 2% N-acetyl glucosamine (NAG) and 4% niacinamide (Olay® Definity®)
- Recently shown to reduce facial hyperpigmentation in Japanese and Caucasian subjects with facial hyperpigmentation in two double-blind, vehicle-controlled, split-face, left-right randomized clinical studies.[Bissett D, et al. Topical Nacetyl glucosamine reduces the appearance of hyperpigmented spots on human facial skin. Presented at: the 64th Annual Meeting of the American Academy of Dermatology, San Francisco, CA; March 3-7, 2006. Poster#236.]
- In another double-blind, vehicle controlled, full-face, clinical study, a significant reduction in facial hyperpigmented spots was seen in patients with facial hyperpigmentation using the NAG 2% + niacinamide 4% formulation when compared with the vehicle regimen.[Kimball AB, et al. Topical formulation containing N-acetyl glucosamine and niacinamide reduces the appearance of hyperpigmented spots on human facial skin. Presented at: the 64th Annual Meeting of the American Academy of Dermatology, San Francisco, CA; March 3-7, 2006. Poster #235.]
- There were no adverse effects reported in any of the studies.
- Improvement seen in 4-8 weeks.
Other topical therapies have been used including ascorbic acid, licorice extract, and in the past, mercury.[Rendon M, et al.
J Am Acad Dermatol 54(5 Suppl):S272-81 (2006).]
*This article was adapted from Lynde CB, Kraft JN, Lynde CW. Melasma and postinflammatory hyperpigmentation and their
treatments. Skin Therapy Lett 11(9):1-4 (2006 Nov).